PROJECT SUMMARY/ABSTRACT Approximately half of all obstructive sleep apnea (OSA) patients cannot tolerate continuous positive airway pressure (CPAP) therapy. Therefore, new treatment options are badly needed. One potential treatment target is the respiratory arousal threshold. Recent evidence suggests that premature arousals to respiratory stimuli (wake up easily to CO2) can prevent important neuromuscular compensatory mechanisms from stabilizing the upper airway. However, effective sedatives for raising the arousal threshold without also reducing pharyngeal muscle tone (a limitation of traditional benzodiazepines), are lacking. Therefore, a major objective of this grant is to find sedatives that will raise the arousal threshold without compromising pharyngeal muscle tone. Another potential treatment target for OSA is the pharyngeal muscles themselves. New animal data suggests that the pharyngeal muscles become hypotonic during sleep primarily because of progressive withdrawal of noradren- ergic tone at the hypoglossal nucleus, as well as muscarinic inhibition during REM sleep. However, due to the relatively recent awareness of these mechanisms, drugs with these neurotransmitter profiles have not been adequately tested in humans. Thus, another major objective of this grant is to identify noradrenergic and anti- muscarinic drugs that can stimulate the pharyngeal muscles during sleep in humans. Lastly, it is hypothesized that treating both traits simultaneously, i.e. combination therapy, may achieve more success than single drug therapy. The rationale for doing this is that non-CPAP therapies (oral appliances, surgery, positional therapy) generally tend to have small effect sizes, and it is realistic to think that these drugs will also. Therefore, com- bining them could maximize their effectiveness and enhance neuromuscular compensation of the pharyngeal muscles. Specifically, Aim 1 will test how well the following drugs stimulate the pharyngeal muscles in sleeping humans: 1) desipramine (a tricyclic antidepresseant with dual noradrenergic and antimuscarinic effects); and 2) atomoxetine (a norepinephrine reuptake inhibitor) in combination with oxybutynin (an antimuscarnic drug). Aim 2 will test the effectiveness of eszopiclone or tiagabine at raising the respiratory arousal threshold. Eszopiclone is a non-benzodiazepine sedative that produces less pharyngeal hypotonia than older sedatives, and tiagabine is and anticonvulsant that induces slow wave sleep. Slow wave sleep is relatively protected from OSA, pre- sumably because it is associated with a higher arousal threshold and more active pharyngeal muscles. Finally, Aim 3 will combine a pharyngeal stimulating drug from Aim 1 with a sedative from Aim 2 to treat OSA in pa- tients with a low arousal threshold and non-severe anatomical compromise (approximately 1/3 of OSA pa- tients). The long term goal is to improve compliance, quality of life, and health outcomes in patients with OSA. This grant is a major first step in achieving this goal and could potentially change the way OSA is managed for many patients.